PROJECT SUMMARY/ABSTRACT Alzheimer's disease (AD) and its related dementias are a significant public health burden that afflicts an estimated 5.7 million people in the United States alone and approximately 10% of those ages 65 and over. Despite these alarming statistics, treatment options are limited, and those that do exist are mostly geared toward mitigating symptoms rather than reversing the underlying pathology. Several lines of evidence indicate that neurofibrillary tangles (NFTs) composed of the microtubule-associated protein tau occur in a part of the brainstem known as the dorsal raphe nucleus (DRN) early on in the course of AD, and that this may lead to the loss of 5-HT neurons. Similar attrition of 5-HT neurons in the DRN has also been observed in alcohol use disorders (AUDs), suggesting that convergent mechanisms may lead to dementia in both. Given that AUDs in older adults have risen in the past decade, we asked whether heavy alcohol use could accelerate the development of AD by enhancing the accumulation of tau in the DRN, which may act as a ?seed? that helps to spread tau pathology throughout the rest of the brain. The goal of this proposal is to elucidate this interaction between heavy alcohol use and the development of tau pathology in the DRN in humanized microtubule associated protein tau (htau) mice. In Specific Aim 1, we will determine whether chronic ethanol exacerbates tau accumulation in 5-HT neurons and heightens depressive-like behaviors in htau mice. In Specific Aim 2, we will determine whether these effects of ethanol on tau pathology are driven by enhanced neuronal activity of 5-HT neurons using optogenetic and chemogenetic approaches in SERT-cre x htau mice. Together, these experiments will reveal neural mechanisms that drive the spread of tauopathies in the brain and facilitate the progression of AD.